Proteasomes are essential for protein homeostasis and proper neuronal function throughout life. This new application focuses on studying a newly discovered neuronal specific abundant proteasome complex and its link to neuronal function in health and aging related neurodegenerative disease. Based on extensive original findings, our central hypothesis is that neuronal activity promotes the degradation of newly synthesized proteins through a transmembrane-like proteasome complex in order to rapidly generate biologically meaningful peptides that are critical for normal nervous system function and appear protective against neurodegenerative processes. The rationale for the proposed research is that nothing is known about this new form of protein homeostasis and further understanding is critical in providing vital insight into neuronal functions mediated by protein degradation. Given the critical importance of protein degradation to human health, the long-range objective of the proposed research is to understand the regulation and function of this degradation program and to apply this knowledge to the detection and eventual treatment of cognitive disorders. Specifically: Aim 1. To identify and study molecular components required for NMP complex assembly and function, to test our hypothesis that a glycoprotein mediates transmembrane like association of the proteasome in the neuronal plasma membrane, which is critical for promoting NMP mediated peptide release and is in part controlled by the disease causing ??amyloid protein; Aim 2. To identify and study specific NMP peptide-receptor interactions relevant to neuronal signaling, to test our hypothesis that distinct amino acid sequences within NMP substrates are critical for NMP dependent degradation into unique peptides that activate NMDAR dependent neuronal signaling and that this interferes with A? induced pathologies; Aim 3. To investigate NMP relevance to neuronal physiology in healthy and diseased brains, to test our hypothesis that inhibition of NMP function affects neuronal physiology and is relevant to nervous system aging and neurodegenerative decline.